PROJECT SUMMARY Passive case finding ? which relies on healthcare workers to determine which patients should be referred for confirmatory TB testing ? remains the predominant approach to TB case finding, resulting in missed or delayed TB diagnosis and ongoing TB transmission within families and communities. In order to achieve the End TB Strategy targets for a 95% reduction in TB deaths and a 90% reduction in TB incidence by 2035, immediate and rapid scale-up of clinic-based active case finding (ACF; provider-initiated symptom screening, followed by Xpert MTB/RIF [Xpert] confirmatory testing) is essential. However, the major barrier to ACF implementation is the low specificity of symptom screening, which makes ACF unaffordable for most high burden countries because the cost to test all symptomatic patients with Xpert testing would consume 20-80% of current TB spending. Thus, there is an urgent need to identify an effective triage test than can limit the proportion of symptomatic patients requiring Xpert testing to those with the highest likelihood of having active TB. The overall objective of this application is to determine whether a triage testing strategy based on C-reactive protein (CRP) levels, measured using a low cost ($2 per test) and rapid (results in 3 minutes) point-of-care (POC) assay could optimize selection of patients for confirmatory TB testing. The central hypothesis is that a TB screening algorithm inclusive of POC CRP triage testing will be more efficient than cough ?2 weeks alone (currently recommended symptom screen) and will thereby enable the efficient use of more sensitive TB screening strategies (e.g., any TB symptom, any cough) to also improve ACF yield. The scientific premise for this hypothesis is based on our own work that identified POC CRP as the first test to meet the minimum sensitivity (?90%) and specificity (?70%) targets established by the WHO for an effective TB screening test among HIV-positive individuals. To test our hypothesis, the study will enroll 1200 HIV-negative outpatients with any TB symptom (cough, fever, night sweats, weight loss) from 4 clinics participating in the CDC-funded TB Trials Consortium (TBTC) Clinical Trials Unit (CTU) in Hanoi, Vietnam. Aim 1 will determine the sensitivity, specificity and predictive values of POC CRP (cut- point 10 mg/L) for culture-confirmed TB among patients who screen positive by 3 symptom-based screening strategies: any TB symptom, any cough and cough ?2 weeks (current recommendation). Aim 2 will perform Xpert Ultra testing in all participants and will identify the optimal TB screening algorithm by comparing the diagnostic yield (proportion of all TB cases detected by Xpert Ultra) and efficiency (number needed to test using Xpert Ultra to detect one case of culture-confirmed TB) of 3 TB screening algorithms combining symptom screening with POC CRP triage testing to 3 TB screening algorithms without POC CRP triage testing (symptom screening alone), and to each other. This research is significant because it has the potential to identify a more efficient and more sensitive TB screening algorithm that would increase TB detection by facilitating efficient scale-up of ACF activities (systematic screening and Xpert Ultra testing) in Vietnam and other target countries. !